PB2366: TRIAL IN PROGRESS: PHASE 1 TRIAL EVALUATING THE SAFETY AND TOLERABILITY OF ODRONEXTAMAB IN COMBINATION WITH CEMIPLIMAB IN RELAPSED/REFRACTORY AGGRESSIVE B-CELL NON-HODGKIN LYMPHOMA
Authors: Cecilia Carmen Carpio Segura, Manjusha Namuduri, Dishan Liu, Nickolas A. Sophos, Min Zhu, Ayesha Sabir, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Alejandro Martin Garcia-Sancho
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Aggressive B-cell non-Hodgkin lymphomas (B-NHLs) progress rapidly. The most common subtype is diffuse large B-cell lymphoma (DLBCL). Current treatment options for relapsed/refractory (R/R) aggressive B-NHLs include additional chemoimmunotherapy, stem cell transplant (autologous [ASCT], or in specific circumstances allogeneic [allo-SCT]), chimeric antigen receptor T cell therapy (CAR T), or an antibody drug conjugate (ADC). However, a notable proportion of pts do not respond to additional chemoimmunotherapy, many pts are ineligible for ASCT, and there is a group of pts that are refractory or progress after CAR T and ADC. Novel treatment combinations are urgently needed. Odronextamab is an off-the-shelf CD20xCD3 bispecific antibody that triggers T-cell-mediated toxicity of malignant B cells. In the Ph 2 ELM-2 (NCT03888105) study, odronextamab demonstrated clinically important anti-tumor activity and a generally manageable safety profile with the optimized step-up (0.7/4/20 mg) regimen in pts with heavily pre-treated R/R DLBCL (Kim, et al. ASH, 2022). Cemiplimab (REGN2810) is a human IgG4 monoclonal antibody directed against PD-1, blocking PD-1/PD-L1-driven inhibitory T-cell signaling. Combining odronextamab and cemiplimab provides an attractive therapeutic opportunity to improve anti-tumor efficacy while restricting T-cell exhaustion in previously treated aggressive B-NHL. Aims: To evaluate safety, tolerability, dose-limiting toxicity (DLT), and anti-tumor activity of odronextamab plus cemiplimab in pts with R/R aggressive B-NHL. Methods: This is a Ph 1, open-label, multicenter, dose escalation and expansion study. Intravenous (IV) odronextamab is given as an induction treatment for 4 cycles, with a step-up dosing schedule undertaken during Cycle (C) 1 to mitigate the risk of cytokine release syndrome (Figure). Full dose odronextamab is administered on D1, D8, and D15 of C2–C4, switching to Q3W during maintenance (C5+). Cycles are 21 days long. IV cemiplimab Q3W at the specified dose level (DL1–DL7; no intra-pt dose escalation) starts on C2D15 after odronextamab step-up regimen is completed and tolerated, to mitigate the risk of additive toxicity. The DLT period will be 28 days from the beginning of cemiplimab administration. During maintenance, cemiplimab dose and schedule is the same as that assigned and tolerated during induction. Maintenance continues until disease progression or other reason for discontinuation. Pts enrolled in the dose expansion portion of the trial receive the recommended Ph 2 dose (RP2D) regimen of the combination treatment. Eligible pts are aged ≥18 yrs with aggressive CD20+ B-NHL (DLBCL, HGBL ± MYC and BCL2 or BCL6 translocations, PMBCL, T/HRBCL, and FL3b) that is R/R after ≥2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Pts must also have measurable disease, ECOG status ≤1, and adequate bone marrow and organ function. Exclusion criteria include primary CNS lymphoma, active infection, prior allo-SCT, ongoing or recent autoimmune disease, and history of severe treatment-related immune adverse events from anti-PD-1/PD-L1 therapy. All pts provide informed consent. Results: Primary endpoints are safety, tolerability, DLTs, and to determine the RP2D regimen of combination odronextamab and cemiplimab. Secondary endpoints include pharmacokinetics of the drugs in combination, immunogenicity, and preliminary anti-tumor activity (ORR, CR rate, and DOR). Summary/Conclusion: This Ph 1 trial is determining the tolerability and preliminary clinical efficacy of odronextamab plus cemiplimab to treat pts with R/R aggressive B-NHL.Keywords: Bispecific, Non-Hodgkin’s lymphoma, Phase I, Monoclonal antibody